Injection is a common technique to deliver a biologically or pharmaceutically active substance, e.g. a vaccine or an antibiotic, to vertebrates such as mammals. However, the process of injection is cumbersome and causes many health problems around the world (cf. for example G.G.P. van de Wijdeven, “Development and assessment of mini-projectiles as drug kinetic implants”, J. Controlled Release 85, 145-162, 2002). In the art, various systems have been developed which partially avoid such problems. In particular, such systems do often not require reconstitution of the biologically or pharmaceutically active material and do not involve any physical contact between the vertebrate and the delivery device. Examples of such techniques include ballistic delivery of, optionally biodegradable, bullets comprising the biologically or pharmaceutically active substance, or powders or microspheres comprising the biologically or pharmaceutically active substance. However, powders and microspheres have as a general disadvantage that they are less efficient than needles.
U.S. Pat. No. 3,948,263, incorporated by reference, discloses a veterinary ballistic implant comprising a biologically or pharmaceutically active substance, e.g. a vaccine. The implant may be made from non-biodegradable materials, e.g. polyolefins, or biodegradable materials, e.g. hydroxypropylcellulose. Similar implants are disclosed in for example U.S. Pat. No. 3,982,536 and U.S. Pat. No. 3,616,758, incorporated by reference herein.
U.S. Pat. No. 4,326,524, incorporated by reference, discloses a veterinary ballistic implant made of mixtures comprising solid, particulate, biologically or pharmaceutically active materials, preferably an antibiotic, and a binder, preferably a water soluble, thermoplastic, cohesive material such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic and the like. A preferred cellulose derivative is hydroxypropylcellulose due to its compatibility with biological systems, its cohesive characteristics and its thermoplasticity. The implant may be provided with a cavity for additional biologically or pharmaceutically active substances.
U.S. Pat. No. 4,449,982, incorporated by reference, discloses a veterinary ballistic implant having a cavity that is filled with a medicament. The medicament may for example be a vaccine, an antibiotic or a small electronic device. If the implant is used for delivering a medicament to an animal intended for human consumption, it is preferred that the implant is made from materials that can be assimilated by the animal body. An example of such a material is a blend of equal mixtures of calcium carbonate and hydroxypropyl cellulose.
WO 87/06129, incorporated by reference, discloses a veterinary ballistic implant comprising a plurality of biodegradable capsules, wherein the biodegradable capsules comprise an effective amount of a physiologically active ingredient, e.g. a vaccine. The implants may be made from materials having an adjuvant function, e.g. water soluble polymers such as polyvinyl pyrrolidone, said materials optionally comprising fillers and extenders. The capsules are preferably made from biologically or pharmaceutically degradable polymers comprising glycolic acid and/or lactic acid.
U.S. Pat. No. 4,664,664 and U.S. Pat. No. 6,375,971, incorporated by reference, disclose a ballistic implant for solid dose medicating of animals. The ballistic implant according to U.S. Pat. No. 6,375,971 comprises a biologically or pharmaceutically compatible bullet having a nose and a body, the latter defining an interior cavity having an interior wall. The surface of the interior wall is provided with means that provide enhanced friction. A cylindrical medicament payload having a size slightly greater than the diameter of the interior cavity is forced into the body of the biologically or pharmaceutically compatible bullet. The bullet is made of a biologically or pharmaceutically inert material that does not cause local tissue reactions and such materials include “GRAS” (“Generally Recognized As Safe”). Suitable GRAS materials are said to be cellulose derivatives, preferably those disclosed in U.S. Pat. No. 4,326,524, incorporated by reference herein. When inside animal's muscle tissue, the bullets are said to disintegrate within a few hours and almost always within 24 hours. The materials for manufacturing the bullet are preferably a polymer blend which may contain fillers, e.g. calcium carbonate, lubricants, e.g. stearic acid. The length of the bullet would not be critical, although longer bullets (i.e. longer than 0.825 inch≈2.096 cm) provide a better accuracy. However, the bullet disclosed in U.S. Pat. No. 6,375,971 has several disadvantages. First of all, the preferred materials for manufacturing the bullet, i.e. hydroxypropyl cellulose and similar materials, are known to have a poor biodegradability as is discussed in U.S. Pat. No. 6,001,385, incorporated by reference. In particular, such materials have undesired side-effects as they often cause inflammations and granulomas. Furthermore, materials like calcium carbonate and stearic acid are known to have an adjuvating effect which is undesired when the implant is intended for human application. Another important disadvantage of the bullet is that the interior surface thereof must be provided with means that provide enhanced friction which requires complicated production steps. Additionally, the size and weight of the bullets according to U.S. Pat. No. 6,375,971 are such that they have too much kinetic energy when fired and are therefore too awkward to be used for human purposes as will be explained in more detail below. Consequently, the bullets disclosed in U.S. Pat. No. 6,375,971 are not very useful and in particular not in human applications.
U.S. Pat. No. 6,001,385, incorporated by reference, and G.G.P. van de Wijdeven, “Development and assessment of mini-projectiles as drug kinetic implants”, J. Controlled Release 85, 145-162, 2002, disclose ballistic implants made of fully destructurised starch, said ballistic implants comprising a biologically or pharmaceutically active material. However, fully destructurised starch (which is the same material as the thermoplastic starch disclosed in G. G. P. van de Wijdeven, “Development and assessment of mini-projectiles as drug kinetic implants”, J. Controlled Release 85, 145-162, 2002) is produced from starch that is subjected to a heat treatment that heats the starch to a temperature above its glass transition and melting temperatures. It has therefore a poor cytotoxicity and poor in vivo degradability properties, presumably due to recrystallisation of the macromolecules formed during the destructurising process thereby making these macromolecules insusceptible or unreachable for hydrolysing enzymes. Additionally, the ballistic implants according to U.S. Pat. No. 6,001,385 do not show tension fields under a polarised light microscope. The relevance of tension fields with respect to biodegradability is discussed in more detail below.
U.S. Pat. No. 6,811,792, incorporated by reference, discloses a solid dosage delivery vehicle suitable for ballistic delivery comprising an outer portion, said outer portion comprising a water soluble, glassy and/or polymeric material, and an hollow compartment comprising a stabilising polyol, most preferably trehalose, and a biologically or pharmaceutically active substance, e.g. a vaccine. Suitable water soluble glasses are said to be those disclosed in WO 90/11756. Preferably, the water soluble glass is a carboxylate derivative of a polyol or a carbohydrate derivative, e.g. trehalose and trehalose octaacetate. The polymeric material may be a polymer or copolymer comprising lactide, glycolide or glucuronide or another polyester, a polyorthoester or a polyanhydride. The compositions used for making the outer portion of the solid dosage delivery vehicle have typically a slow degradation rate which implies that the biologically or pharmaceutically active substance is released in a sustained manner during a period in the order of at least days. The solid dosage delivery vehicle may be in the form of a needle having a diameter in the range of 1-5 μm and a length in the range of 5-150 μm. However, such needles are impractical due to their small size, low weight and low strength.
EP 326.517 A1, incorporated by reference, discloses a process for forming starch into a melt wherein a composition comprising starch and water and having a water content of 5 to 40 wt. %, calculated on the weight of the composition, is extruded at a temperature of 80° to 200,preferably 120° to 190°, more preferably 130° to 190° C., and a pressure of 0 to 15 MPa, preferably 0 to 7.5 MPa and in particular 0 to 5 MPa. The obtained essentially destructurised starch has a water content of 10 to 20 wt. %, more preferably 12 to 19 wt. % and in particular 14 to 18 wt. %. Residence times of the composition within the extruder and mechanical properties of the essentially destructurised starch are not disclosed.
WO 92/15285 discloses that starch melts can be processed to various levels of destructurisation ranging from destructurised starch, molecularly dispersed starch (i.e. a higher level of destructurisation) and thermoplastic starch. It further discloses that the method disclosed in U.S. Pat. No. 4,673,438 (equivalent to EP 118.240 A1) provides substantial destructurisation. The process according to WO 92/15285 involves a temperature of 80° to 240° C., preferably 130° to 160° C., wherein a water content is maintained in the range of 5 to 45 wt. %, preferably 10 to 25 wt. %. Example 1 discloses the extrusion of a mixture comprising potato starch (81% w/w), hydrogenated triglyceride (1% w/w), soya lecithine (0.5% w/w), titanium dioxide (0.5% w/w) and water (17% w/w) following the procedure of U.S. Pat. No. 4,673,438.Example 2 and FIG. 6 disclose that compositions comprising the starch product and a pharmaceutically active substance released the latter more rapidly at higher water contents (ranging from 5% to 17.7%). Example 11 discloses that the degree of destructurisation can be controlled by process parameters (temperature, water content of the starch, amount of shear and processing time) without specifying the effect of these process parameters. FIG. 10 discloses that within a process temperature range of 100° to 160° C. no differences within release rates was observed when compositions comprising the starch product and a pharmaceutically active substance were subjected to a dissolution test. Only when the process temperature employed was 70° C., a more rapid release was observed. Furthermore, mechanical properties of the destructurised starch are not disclosed.
The present invention therefore provides a ballistic or kinetic implant having excellent mechanical properties which rapidly degrades under physiological conditions and which has a very low cytotoxicity.